Cytomegalovirus (CMV) infection is the most common congenital infection in the United States and is a leading cause for hearing loss in children. CMV infection is also a major problem for immunocompromised patients, where CMV infections frequently result in life threatening complications. Unfortunately, existing drugs have poor bioavailability and toxicity profiles which limit their use to only the most critically ill patients. Thus, there is a critical need to develop potent, safe and efficacious drugs for the treatment of CMV. Our laboratory has a long standing interest in the development of medicinal agents directed towards the inhibition key protein-protein interactions involved in critical biological processes. The objective of this application is to develop agents that target a critical, virally-specific protein-protein interaction involved in viral DNA synthesis. Our targeted interaction occurs between the virally encoded polymerase (UL54) and its processivity factor (UL44). Previous studies have shown that this interaction is required for viral viability. The central hypothesis of this R21 grant is that compounds that attach to the UL54-binding pocket of UL44 will inhibit the formation of the UL44:UL54 complex and thus inhibit viral replication. Our hypothesis has been formulated based upon a variety of studies that show that inhibition of the protein-protein interaction between UL44 and UL54 halts viral replication and our preliminary studies which have used computational and rational design to create compounds that inhibit complex formation. Exploration of compounds that inhibit the UL44:UL54 interaction will be done following according to two specific aims: 1. Identify novel inhibitors of the UL54:UL44 complex based upon mimicking the ?-helix of the C-terminus of the UL54 protein. 2. Identify novel inhibitors of the UL54:UL44 complex by in silico pharmacophore screening of databases of commercially available compounds. At the conclusion of this study, we expect that a foundation for a new class of anti-CMV agents will be laid, which in turn, will provide the basis for future intensive medicinal chemistry efforts. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) infection is the most common congenital infection in the United States and major problem for immunocompromised patients. Unfortunately, existing agents to treat CMV are less then ideal. As an outcome of the proposed investigations, we expect to develop new therapeutic agents targeted to the disruption of a critical protein-protein interaction within CMV DNA replication. This contribution is significant because it is expected to provide new anti-CMV agents that will function on a viral target different from existing therapies and once such therapies become available, there is the expectation that these agents will positively impact the treatment of CMV in children and immunocompromised patients. Finally, the information learned during the development of inhibitors of the UL44:UL54 interaction in CMV should be applicable to other herpesviruses which have been demonstrated to require a similar protein-protein interaction. [unreadable] [unreadable] [unreadable]